Coumarin endcapped absorbable polymers

ABSTRACT

The present invention includes photocurable, liquid polymers incorporating coumarin ester endgroups into their molecular structure, which polymers are crosslinked upon irradiation with ultraviolet light by photochemically allowed [2+2] cycloaddition reactions among the chain ends, and which crosslinked polymers are useful in the preparation of medical devices, tissue engineering scaffolds, drug delivery systems and, in particular, in vivo preparation of implants in an open surgical procedure or laproscopically.

FIELD OF THE INVENTION

[0001] The invention relates to photocurable, liquid absorbable polymerscontaining coumarin ester endgroups, medical devices containingcrosslinked coatings of such polymers, and polymeric networks formed bycrosslinking such polymers, including surgical implants, tissueengineering scaffolds, adhesion prevention barriers, soft tissue bulkingor defect filling agents; and drug delivery vehicles.

BACKGROUND OF THE INVENTION

[0002] The field of absorbable biomaterials has been dominated by theuse of purified, naturally occurring polymers such as collagen andthermoplastic polyesters based on five common lactone monomers(glycolide, L-lactide, p-dioxanone, trimethylene carbonate, andε-caprolactone). Homopolymers and simple copolymers of these monomersadequately met the physical and mechanical property requirements of thefirst absorbable sutures and meshes. Then, polymeric blends andsegmented block copolymers were developed to address the need to controlmore precisely not only the physical and mechanical properties of thefibers, but also the in vivo breaking strength retention profile andtotal absorption of these materials. In general, the majority of thesepolymers are strong, stiff thermoplastics that are processed byinjection molding, extrusion, and other common melt processingtechniques.

[0003] Recently, absorbable thermoplastic elastomers have been developedto address the need in medical device development for an elasticmaterial, e.g. U.S. Pat. Nos. 5,468,253 and 5,713,920. In addition,absorbable polymeric liquids and pastes have been developed to increasethe range of physical properties exhibited by the aliphatic polyestersbased on glycolide, lactide, p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one,trimethylene carbonate, and ε-caprolactone, e.g. U.S. Pat. Nos.5,411,554, 5,599,852, 5,631,015, 5,653,992, 5,688,900, 5,728,752 and5,824,333.

[0004] Hubbell et al., in U.S. Pat. Nos. 5,573,934 and 5,858,746,disclosed the use of photocurable polymers to encapsulate biologicalmaterials including drugs, proteins, and cells in a hydrogel. Thehydrogel was formed from a water soluble biocompatible macromercontaining at least two free radical polymerizable substituents andeither a thermal or light activated free radical initiator. An exampleof such a photoreactive system is an acrylate ester endcappedpoly(ethylene glycol) containing ethyl eosin and a tertiary amine. Aftera series of light activated reactions between ethyl eosin and the amine,the acrylate endgroups polymerize into short segments that result in acrosslinked polymeric network composed of poly(ethylene glycol) chainsradiating outward from the acrylate oligomers. The physical andmechanical properties of the resulting hydrogel are dependent on thereproducibility of the free radical oligomerization reaction.

[0005] Hubbell et al. expanded this concept in U.S. Pat. No. 5,410,016in the form of photocurable, segmented block copolymers composed notonly of water soluble segments, such as poly(ethylene glycol), but alsoof segments with hydrolizable groups, in particular, with short segmentsof aliphatic polyesters. In this way, the resulting hydrogel breaks downinto soluble units in vitro and in vivo in a controlled fashion. Thephotochemistry is the same and based on the free radical polymerizationof acrylate and methacrylate endgroups.

[0006] Despite these developments in the field of absorbablebiomaterials, there is a need for thermosetting materials, that is,materials that can be easily applied as low molecular weight compounds,and by a controlled chemical process, crosslink to form a polymericnetwork having physical, mechanical and biological properties determinedby its components.

[0007] Thus, it is an objective of the present invention to provide aphotocurable, absorbable, thermosetting polymer for use in medicalapplications and drug delivery.

SUMMARY OF THE INVENTION

[0008] The present invention is directed to photocurable, fluidprepolymers comprising a polymer prepared from at least one lactonemonomer selected from the group consisting of ε-caprolactone,trimethylene carbonate, glycolide, L-lactide, D-lactide, DL-lactide,p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one, 1,4-dioxepan-2-one and1,5-dioxepan-2-one, said prepolymer being a liquid at 65° C. or at alower temperature and comprising coumarin ester endgroups, wherein theinherent viscosity of the polymer is between about 0.05 dL/g and about0.8 dL/g as determined in a 0.1 g/dL solution of hexafluoroisoproanol at25° C., and wherein the polymer is crosslinked upon irradiation withultraviolet light, and to polymeric networks, microparticles and medicaldevices, each formed by irradiating fluid prepolymers of the presentinvention. The present invention also is directed to methods ofmodifying a surface of a substrate, to methods of forming medicalimplants and to methods of repairing bony defects, each method utilizingthe fluid prepolymers of the present invention. Photocuring of the fluidprepolymers can be conducted manually, for example, in an operating roomby first applying the fluid prepolymer to the desired site and thenirradiating the liquid with an ultraviolet light source effective tocrosslink the polymer. Alternately, photocuring can be conductedautomatically using a computerized instrument, e.g. a stereolithographyapparatus, to make medical devices.

BRIEF DESCRIPTION OF THE FIGURES

[0009]FIG. 1 is the graph plotting the % gel yield as a function of timefor three ultraviolet radiation intensities for polymer E in Table 1.

[0010]FIG. 2 is the graph plotting the weight loss of a crosslinked filmas a function of the time immersed in phosphate buffered saline pH 7.4at 37° C.

[0011]FIG. 3 is the scanning electron micrograph of a square made byusing coumarin ester endcapped, liquid absorbable polymers as aphotoresist material.

DETAILED DESCRIPTION OF THE INVENTION

[0012] The ring opening polymerization of lactone monomers has beenwidely studied, and the resulting aliphatic polyesters have been meltprocessed by extrusion and injection molding into many commercialmedical devices such as sutures, suture anchors, ribbons, plates, pins,screws, rods, and staples. The most common monomers are glycolide,L-lactide, DL-lactide, p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one,trimethylene carbonate and ε-caprolactone, and, except forpoly(trimethylene carbonate) which is amorphous and above its glasstransition temperature at 37° C., all of the resulting homopolymers arematerials with useful physical, mechanical and biological properties.Nonetheless, there are many manufacturing processes and medicalapplications in which these thermoplastic polymers can not be employedbecause of their high viscosity, solubility or insolubility, thermalinstability, crystallization kinetics, and phase separation phenomena.For these reasons and others, in the field of commodity plastics,thermosetting resins were developed. Thermosetting resins usually areprepared from low molecular weight compounds that react when mixedtogether or exposed to a stimulus such as heat, light, the addition of acatalyst or an initiator. Thermosetting resins typically are not meltprocessed, but rather are used at ambient or near ambient temperatures.The components of a thermosetting system react to form a polymericnetwork that exhibits excellent mechanical properties. In fact, there isexcellent control of those properties by varying the type and amount ofthe components. In the present invention, liquid absorbable polymersmade by the ring opening polymerization of lactone monomers aretransformed into photocurable, thermosetting materials by an endcappingreaction that converts the hydroxyl endgroups into coumarin esterendgroups which are capable of undergoing a [2+2] cycloadditiondimerization reaction.

[0013] As disclosed in U.S. Pat. Nos. 5,411,554, 5,599,852, 5,631,015,5,653,992, 5,728,752, and 5824,333, low molecular weight polyesters aresynthesized in the same manner as high molecular weight polymers fromtheir corresponding lactone monomers. To illustrate this, the chemicalequation describing the synthesis of a liquidpoly[ε-caprolactone-co-trimethylene carbonate] is shown below. R(OH)_(n)represents a generic polyol as the initiator, Sn(oct)₂ represents tin(II) 2-ethyl-hexanonate as the Lewis acid catalyst, and P(OH)_(n)represents the liquid absorbable polymer.

[0014] The molar ratio of the sum of the monomers in a reaction to theamount of initiator added controls the molecular weight of the resultingpolymer. Consequently, the synthesis of low molecular weight, liquidabsorbable polymers involves adding more initiator to the reaction thanwhen high molecular weight materials are desired, barring anythermodynamic problems caused by a high concentration of chain ends.Branched liquid absorbable polymers can also be prepared by usingmultifunctional initiators such as trimethylolpropane, pentaerythritol,branched poly(ethylene glycol)s, oligomeric poly(2-hydroxyethylmethacrylate, poly(vinyl alcohol), poly(vinyl alcohol-co-vinyl acetate),or any other polyol. In fact, these multifunctional initiators can beused in conjunction with diols like ethylene glycol, 1,2-propyleneglycol, 1,3-propanediol, diethylene glycol, linear poly(ethyleneglycol)s, linear poly(propylene glycol)s, and linear poly(ethyleneglycol-co-propylene glycol)s. Liquid absorbable polymers can besegmented block copolymers by adding different lactone monomers ordifferent mixtures of lactone monomers sequentially to the reaction. Twoor more unique liquid absorbable polymers can be mixed together and usedto tailor the mixture's physical properties.

[0015] For the purposes of this invention, liquid absorbable polymerwill mean any linear or branched polymer or mixture of polymers, of anypossible microstructure (statistically random or segmented block),prepared from at least one lactone monomer which is a fluid at 65° C. orlower.

[0016] These liquid absorbable polymers are converted into aphotocurable, thermosetting resin by converting the hydroxyl endgroupsby any conceived synthetic route into a coumarin derivative. Althoughthere are many possible endcapping reagents that could be prepared toaccomplish this functionalization of the liquid absorbable polymer, thepreferred endcapping agent is 7-chlorocarbonylmethoxycoumarin. Thepreferred synthesis of 7-chlorocarbonylmethoxycoumarin, as well as theendcapping reaction with a liquid absorbable copolymer, is shown below.

[0017] The endcapping reaction does not alter the physical state of theliquid absorbable polymer (still fluid at 65° C.) thereby providing aneasy to use liquid that can be injected, pumped, spread, sprayed, ordissolved as 10 required by the manufacturing process. When thesecoumarin ester endcapped, liquid absorbable polymers are irradiated withultraviolet light, the coumarin endgroups undergo a photochemicallyallowed, [2+2] cycloaddition dimerization reaction as depicted below.

[0018] This cycloadditon reaction covalently bonds two polymerstogether. For a linear (difunctional) liquid absorbable polymer, theresult is an increase in the molecular weight of the material. In thecase when a blend of at least two compositionally different, linear,coumarin ester endcapped, liquid polymers are used, the result is theformation of a linear segmented block copolymer. For a branched(multifunctional>2) liquid absorbable polymer, the result is theformation of a polymeric network. In contrast to many other kinds ofcrosslinking chemistry, the coumarin dimerization reaction requires noadditives, catalysts, intiators, or sensitizers which makes the systemmore elegant as well as safer when used in vivo.

[0019] Therefore, the present invention describes a fluid prepolymercomprising a polymer prepared from at least one lactone monomer selectedfrom the group consisting of ε-caprolactone, trimethylene carbonate,glycolide, L-lactide, D-lactide, DL-lactide, p-dioxanone,5,5-dimethyl-1,3-dioxan-2-one, 1,4-dioxepan-2-one and1,5-dioxepan-2-one, said prepolymer being a liquid at 65° C. or at alower temperature and comprising coumarin ester endgroups, wherein theinherent viscosity of the polymer is between about 0.05 dL/g and about0.8 dL/g as determined in a 0.1 g/dL solution of hexafluoroisoproanol at25° C., that reacts upon exposure to ultraviolet light to form apolymeric network or a segmented block copolymer depending on theoverall functionality and photoconversion. The photocuring can becarried out manually, for example, in an operating room by firstapplying the fluid prepolymer to the desired site and then irradiatingthe liquid with an ultraviolet light source, or can be carried outautomatically using a computerized instrument such as astereolithography apparatus to make medical device prototypes.

[0020] In another embodiment of the present invention, a method ofsurface modification is disclosed comprising forming a film of the fluidprepolymer, said prepolymer comprising a polymer prepared from at leastone of lactone monomer selected from the group consisting ofε-caprolactone, trimethylene carbonate, glycolide, L-lactide, D-lactide,DL-lactide, p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one,1,4-dioxepan-2-one and 1,5-dioxepan-2-one, said prepolymer being aliquid at 65° C. or at a lower temperature and comprising coumarin esterendgroups, wherein the inherent viscosity of the polymer is betweenabout 0.05 dL/g and about 0.8 dL/g as determined in a 0.1 g/dL solutionof hexafluoroisoproanol at 25° C., on the substrate and irradiating withthe film with ultraviolet light effective to form a crosslinked coating.Such a coating on a medical device can be employed to modify the surfaceproperties of the implant, thereby controlling the cellular interactionsand modifying the absorption profile of absorbable devices. A templatemay be used to direct the ultraviolet light to only certain areas of thecoated substrate. In this way, a surface architecture can be formed onthe substrate akin to the photoresists of the electronics industry.

[0021] In another embodiment of the present invention, a fluidprepolymer comprising a polymer prepared from at least one lactonemonomer selected from the group consisting of ε-caprolactone,trimethylene carbonate, glycolide, L-lactide, D-lactide, DL-lactide,p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one, 1,4-dioxepan-2-one, and1,5-dioxepan-2-one, said prepolymer being a liquid at 65° C. or at alower temperature and comprising coumarin ester endgroups, wherein theinherent viscosity of the polymer is between about 0.05 dL/g and about0.8 dL/g as determined in a 0.1 g/dL solution of hexafluoroisoproanol at25° C., that reacts upon exposure to ultraviolet light to form apolymeric network, and at least one bioactive compound, is disclosed forthe sustained release of the entrapped drugs. Medical devices such asstents and catheters coated in this fashion become bioactive medicaldevices with a drug delivery component in addition to any surfacemodifications mentioned previously. Drug containing microparticles alsocan be formed by irradiating droplets of the fluid prepolymer comprisingdissolved or suspended drugs and other biologically active substances.

[0022] The variety of different therapeutic agents that may be used inconjunction with the coumarin ester endcapped, liquid polymers of theinvention is vast. In general, therapeutic agents which may beadministered via the pharmaceutical compositions and coatings of theinvention include, without limitation, anti-infectives such asantibiotics and antiviral agents, analgesics and analgesic combinations,anorexics, antihelmintics, antiarthritics, antiasthmatic agents,anticonvulsants, antidepressants, antidiuretic agents, antidiarrheals,antihistanimes, anti-inflammatory agents, antimigraine preparations,antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics,antipsychotics, antipyretics, antispasmodics, anticholinergics,sympathomimetices, xanthine derivatives, cardiovascular preparationsincluding calcium channel blockers and beta-blockers such as pindololand antiarrhymics, antihpertensives, diuretics, vasodilators includinggeneral coronary, peripheral and cerebral, central nervous systemstimulants, cough and cold preparations, including decongestants,hormones such as estradiol and other steroids including corticosteroids,hypnotics, immunosuppressives, muscle relaxants, parasympatholytics,psychostimulants, sedatives, and tranquilizers, and naturally derived orgenetically engineered proteins, polysaccharides, glycoproteins, orlipoproteins. Suitable pharmaceuticals for parenteral administration arewell known as is exemplified by the Handbook on Injectable Drugs, 6^(th)edition, by Lawrence A Trissel, American Society of HospitalPharmacists, Bethesda, Md., 1990 (hereby incorporated by reference).

[0023] Parenteral administration of a drug formulation of the inventioncan be affected by the injection of the mixture of drug and coumarinester endcapped, liquid polymer and then photocured in situ, or by theinjection of suspended, drug filled microparticles made by dissolving ormixing the drug in the coumarin ester endcapped, liquid polymer,dispersing this mixture to form small droplets, irradiating thosedroplets to form a crosslinked network, thereby entrapping the drug inthe polymeric matrix, suspending these particles in a suitable fluid asa carrier, and then injecting that suspension into the body.

[0024] Parenteral formulations of the copolymers may be formulated bymixing one or more therapeutic agents with the liquid copolymer. Thetherapeutic agent may be present as a liquid, a finely divided solid, orany other appropriate physical form. Drug excipients and stabilizers mayalso be added to the mixture of liquid absorbable polymer and bioactivecompound to produce a therapeutic product with sufficient shelf life tobe safe and sold commercially.

[0025] Similar formulations can also be used in oral drug deliveryformulations. In this case, the drug filled particles or solid form isplaced in a capsule or is coated with a suitable barrier layer to passthrough the stomach and into the intestine. Sometimes, the capsule orcoating may not be necessary or desirable.

[0026] The amount of therapeutic agent will be dependent upon theparticular drug employed and the medical condition being treated.Typically, the amount of drug represents about 0.001% to about 75%, moretypically from about 0.001% to about 50%, and most typically from about0.001% to about 25% by weight of the total composition.

[0027] The quantity and type of copolymers incorporated into theparenteral formulation will vary depending on the release profiledesired and the amount of drug employed. For a more viscous composition,generally a higher molecular weight polymer is used. If a less viscouscomposition is desired, a lower molecular weight polymer can beemployed. The product may contain blends of liquid copolymers to providethe desired release profile or consistency to a given formulation. Infact, the molecular weight and its distribution of the coumarin esterendcapped, liquid absorbable polymer also determines the crosslinkdensity of the resulting polymeric network, because the individualpolymer chains are simply bonded together at their ends by [2+2]cycloaddition reactions without any side reactions. The higher theinitial molecular weight of the coumarin ester endcapped, liquidpolymer, the longer the segment length (the number of bonds betweencrosslinks) of the resulting polymeric network, the lower the crosslinkdensity. Many physical and mechanical properties like stiffness andelasticity depend on the crosslink density of the network and can betailored by choosing the chemical composition and molecular weight theprecursor liquid polymer to match the desired properties.

[0028] Individual formulations of drugs and coumarin ester endcapped,liquid absorbable polymers may be tested in appropriate in vitro and invivo models to achieve the desired drug release profiles. For example, adrug could be formulated with the coumarin ester endcapped, liquidabsorbable polymer, photocured into a coating or particles, andimplanted into an animal. The drug release profile could then bemonitored by appropriate means such as by taking blood samples atspecific times and assaying those samples for drug concentration.Following this or similar procedures, those skilled in the art will beable to formulate a variety of sustained release parenteralformulations.

[0029] In another embodiment of the present invention, a method offorming medical implants by irradiating the fluid prepolymer, comprisinga polymer prepared from at least one lactone monomer selected from thegroup consisting of ε-caprolactone, trimethylene carbonate, glycolide,L-lactide, D-lactide, DL-lactide, p-dioxanone,5,5-dimethyl-1,3-dioxan-2-one, 1,4-dioxepan-2-on and 1,5-dioxepan-2-one,said prepolymer being a liquid at 65° C. or at a lower temperature andcomprising coumarin ester endgroups, wherein the inherent viscosity ofthe polymer is between about 0.05 dL/g and about 0.8 dL/g as determinedin a 0.1 g/dL solution of hexafluoroisoproanol at 25° C., in vivo isprovided. In this way, polymeric networks with custom shapes are formedduring surgery to prevent adhesions, to bulk tissue, or to fill tissuedefects. Since the fluid prepolymer is a liquid, it can be applied tothe surgical site by injection and subsequently cured by exposure toultraviolet radiation. This series of steps may be conductedlaproscopically through an appropriately design applier comprising aninjection system and fiber optic light source, or more conveniently, inan open procedure with a syringe and light source.

[0030] In another embodiment of the present invention, a fluidprepolymer comprising a polymer prepared from at least one lactonemonomer selected from the group consisting of ε-caprolactone,trimethylene carbonate, glycolide, L-lactide, D-lactide, DL-lactide,p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one, 1,4-dioxepan-2-one and1,5-dioxepan-2-one, said prepolymer being a liquid at 65° C. or at alower temperature and comprising coumarin ester endgroups, wherein theinherent viscosity of the polymer is between about 0.05 dL/g and about0.8 dL/g as determined in a 0.1 g/dL solution of hexafluoroisoproanol at25° C., and at least one inorganic compound, is disclosed for use as abone filler. The number of inorganic compounds that can be used islarge. The following inorganic compounds are widely used in biomedicalapplications and can be incorporated as components of the bone filler ofthis invention: alpha-tricalcium phosphate, beta-tricalcium phosphate,calcium carbonate, barium carbonate, calcium sulfate, barium sulfate,and hydroxyapatite. In this application, the ceramic or glass filledprepolymer is placed in a boney defect with or without bone fragmentsfrom the patient and then irradiated to form a temporary defect fillerthat will not flow out of the desired surgical site. Drugs and growthfactors may also be incorporated into the formulation of fluidprepolymer and inorganic compound.

[0031] The following examples illustrate, but are not intended to limit,the scope of the claimed invention.

EXAMPLE 1

[0032] Synthesis of 7-Coumarin Ethyl Acetate Ether

[0033] 20.3 grams (0.125 mol) of 7-hydroxycoumarin, 24.7 grams (0.179mol) of potassium carbonate, 25.0 grams (0.150 mol) of ethylbromoacetate, and 450 mL of dry acetone were added to a 500 mL roundbottom flask containing a magnetic stirrer bar. The reaction mixture wasstirred and refluxed for 2 hours under a N₂ atmosphere. The byproduct,potassium bromide, was removed by filtration, and the solvent removed bydistillation on a rotary evaporator. The crude product wasrecrystallized from ethanol and vacuum dried. The yield was 27.7 grams(89%). ¹H NMR (270 MHz, DMSO-d₆, ppm) δ 1.18 (3H, triplet, J=8.1 Hz),4.16 (2H, quartet, J=8.1 Hz), 4.91 (2H, singlet), 6.28 (1H, doublet,J=9.9 Hz), 6.96 (1H, doublet, J=2.0 Hz), 6.98 (1H, quartet, J=2.0, and8.9 Hz), 7.61 (1H, doublet, J=8.9 Hz), 7.96 (1H, doublet, J=9.9 Hz).

EXAMPLE 2

[0034] Synthesis of 7-Coumarin Acetic Acid Ether

[0035] 6.92 grams (27.9 mmol) of 7-coumarin ethyl acetate ether and 280mL of 1,4-dioxane were added to a 1 L Erlenmeyer flask containing amagnetic stirrer bar. 400 mL of water containing 16.2 grams (0.405 mol)of sodium hydroxide was added to this flask, and the mixture solutionwas stirred overnight at room temperature. The solution was acidifiedwith concentrated hydrochloric acid, and organic compounds wereextracted into a mixture of chloroform and methanol. These solvents werethen removed by distillation under reduced pressure. The resulting crudeproduct was recrystallized from ethanol; the yield was 5.51 grams (90%).¹H NMR (270 MHz, DMSO-d₆, ppm) δ 4.83 (2H, singlet), 6.28 (1H, doublet,J=9.9 Hz), 6.95 (1H, doublet, J=2.0 Hz), 6.97 (1H, doublet, J=2.0, and8.9 Hz), 7.62 (1H, doublet, J=8.9 Hz), 7.97 (1H, doublet, J=9.9 Hz),13.13 (1H, s).

EXAMPLE 3

[0036] Synthesis Of 7-Chlorocarbonylmethoxycoumarin

[0037] 3.76 g (17.1 mmol) of 7-coumarin acetic acid ether and 20.0 mL(0.277 mol) of thionyl chloride were added to a 300 mL round bottomflask containing a magnetic stirrer bar. A water cooled condenser wasattached to this flask, and the reaction mixture was stirred andrefluxed for 3 hours under a N₂ atmosphere. The excess thionyl chloridewas removed by distillation, and crude product was isolated. The yieldwas 4.00 grams (98%).

[0038]¹H NMR (270 MHz, DMSO-d₆, ppm) δ 4.83 (2H, singlet), 6.28 (1H,doublet, J=9.9 Hz), 6.94(1H, doublet, J=2.0 Hz), 6.96 (1H, quartet,J=2.0, and 8.9 Hz), 7.62 (1H, doublet, J=8.9 Hz), 7.97 (1H, doublet,J=9.9 Hz).

EXAMPLE 4

[0039] Synthesis of Poly (ε-caprolactone-co-trimethylene carbonate)P[CL/TMC]

[0040] The liquid absorbable polymers of this invention can be preparedas disclosed in U.S. Pat. No. 5,411,554, 5,468,253, 5,599,852,5,631,015, 5,653,992, 5,728,752, and 5,824,333. A typicalcopolymerization reaction is described below.

[0041] 125 μL (43 μmol) of a 0.33 M stannous 2-ethylhexanoate solutionin toluene, 4.38 grams (32.6 mmol) of trimethylolpropane, 64.0 grams(0.627 mol) of recrystallized trimethylene carbonate, and 71.8 grams(0.629 mol) of vacuum distilled ε-caprolactone were transferred into asilanized, flame dried, 300 mL round bottom flask equipped with astainless steel mechanical stirrer and a nitrogen gas blanket. Thereaction flask was placed in an oil bath already set at 180° C. and heldthere for 8 hours. The stirrer blade was lifted out of the liquidpolymer solution and replaced with an inlet adapter attached to aFirestone valve. The polymer was then devolatized under vacuum at 90° C.for 36 hours. The branched, statistically random copolymer was isolatedby pouring into a glass jar. The yield was 139.0 grams (99%). Polymer Ein Table 1. M_(n)=8,170 g/mol (polyethylene glycol standard; eluent,DMF). FTIR (KBr, cm⁻¹) 3529, 2955, 2866, 1744, 1252, 1164, and 1036. ¹HNMR (270 MHz, CDCl₃, ppm) δ 1.37 (2H, multiplet), 1.62 (4H, multiplet),2.01 (2H, multiplet), 2.27 (2H, multiplet), and 4.20 (6H, multiplet).

[0042] Trimethylene carbonate was recrystallized from a mixture of ethylacetate and n-hexane. Other solvents and reagents were obtainedcommercially and were purified by distillation or recrystallization. ¹HNMR spectra were measured on a JEOL JNM-GX270 FT-NMR spectrometer. Thechemical shifts were given in 6 values from Me₄Si as an internalstandard. IR spectra were measured on a Shimadzu DR-8020 FT-IRspectrophotometer. UV absorption spectra were measured on a JASCOUbest-30 UV/VIS spectrophotometer. The molecular weight of polymer wasestimated by GPC analysis which was carried out on a Toso SC-8020.

EXAMPLE 5

[0043] Synthesis of Coumarin Ester Endcapped P[CL/TMC]

[0044] A typical endcapping reaction is described below. 1.05 grams(0.129 mmol) of P[CL/TMC] as prepared in Example 4, 0.427 grams (1.79mmol) of acetyl chloride 7-coumarin as prepared in example 3, 0.050 mL(0.62 mmol) of pyridine, and 20.5 mL of dichloromethane were added to a100 mL round bottom flask containing a magnetic stirrer bar. Thereaction mixture was stirred overnight at room temperature under a N₂atmosphere. The resulting coumarin ester endcapped P[CL/TMC] wasisolated by precipitation in diethyl ether and purified by fractionationwith DMF and 8::2 diethyl ether:methanol. The yield was 0.99 grams(86%). FTIR (KBr, cm⁻¹) 2953, 2866, 1743, 1614, 1250, 1164, and 1036. ¹HNMR of coumarin groups (270 MHz, CDCl₃, ppm) δ 4.69 (2H, doublet), 6.26(1H, doublet, J=9.3 Hz), 6.79 (1H, doublet, J=2.4 Hz), 6.87 (1H,quartet, J=2.4, and 8.3 Hz), 7.39 (1H, doublet, J=8.3 Hz), 7.62 (1H,doublet, J=9.3 Hz).

[0045] Assuming 100% conversion of the hydroxyl endgroups of the liquidabsorbable copolymers into coumarin esters, UV spectroscopy could beused to estimate the equivalent weight of the resulting photocurablepolymer and subsequently its molecular weight by simple multiplicationby the number of branches. A typical measurement was conducted asfollows. 10 miligrams of coumarin ester endcapped copolymer wasdissolved in 40.0 mL of DMF, and UV spectrum measured. The coumarincontent was calculated from the value of UV absorption [ε_(max) ofcoumarin=1.35×10⁴]. For example, the equivalent weight of the endcappedcopolymer of example 4 was 3.65×10⁻⁴ mol/g.

[0046] The polymerization and endcapping results are summarized in Table1.Table 1. Polymers and Endcapping

[0047] Results Molar Molar Composition OH value Exp InitiatorFraction^(a) N^(b) (CL:TMC) MW^(c) (mol/g)^(d) MW^(e) A CH₂(CH₂OH)₂0.076 2 49/50 3200 B PEG1000 0.076 2 50/50 4700 3.40 × 10⁻⁴ 5800 CCH₃CH₂C(CH₂OH)₃ 0.152 3 51/49 2900 8.34 × 10⁻⁴ 3600 D CH₃CH₂C(CH₂OH)₃0.114 3 50/50 4200 5.88 × 10⁻⁴ 5100 E CH₃CH₂C(CH₂OH)₃ 0.076 3 50/50 81003.22 × 10⁻⁴ 9300 F CH₃CH₂C(CH₂OH)₃ 0.049 3 50/50 12400 3.00 × 10⁻⁴ 10000G CH₃CH₂C(CH₂OH)₃ 0.076 3 59/41 6100 3.52 × 10⁻⁴ 8500 H CH₃CH₂C(CH₂OH)₃0.076 3 39/61 5900 3.55 × 10⁻⁴ 8500 I CH₃CH₂C(CH₂OH)₃ + 0.075 3/2 50/505400 PEG600 (1:1) J CH₃CH₂C(CH₂OH)₃ 0.076 3  0/100 4800 5.77 × 10⁻⁴ 5200K C(CH₂OH)₄ 0.260 4 49/51 2800 1.26 × 10⁻³ 3200 L C(CH₂OH)₄ 0.152 449/51 5300 7.90 × 10⁻⁴ 5100 M C(CH₂OH)₄ 0.076 4 50/50 13800 3.39 × 10⁻⁴11800 N C(CH₂OH)₄ 0.152 4  0/100 4200 8.00 × 10⁻⁴ 5000 O C(CH₂OH)₄ 0.1524 27/73 4800 8.04 × 10⁻⁴ 5000 P C(CH₂OH)₄ 0.152 4  7/93 4600 8.00 × 10⁻⁴5000 Q C(CH₂OH)₄ 0.152 4 76/24 3800 8.07 × 10⁻⁴ 5000 R b-PEG^(f) 0.152 450/50 7400 5.71 × 10⁻⁴ 7000

[0048]

EXAMPLE 6

[0049] Network Formation by Irradiation

[0050] The typical procedure for photogelation of these coumarin esterendcapped, liquid absorbable polymers is discussed below.

[0051] 40 milligrams of coumarin end-capped polymer was dissolved in1.00 mL of dichloromethane, 150 μL of this solution was dropped on acover glass (diameter 14.5 mm), and then the dichloromethane was removedunder reduced pressure to prepare a thin film having a thickness of 0.03mm. The film was irradiated with ultraviolet light (Hg—Xe lamp) ofvarying intensity and time. The polymeric network or gel that formed waswashed with dichloromethane and dried under reduced pressure to constantweight. The gel was weighed and gel yield calculated. FIG. 1 shows aplot of the gel yield as a function of time for three ultravioletradiation intensities for polymer E in Table 1. Clearly, the rate ofphotocuring is dependent on the ultraviolet intensity, but atapproximately 100 mW/cm³, gelation is completed in less than two minutesat this thickness.

EXAMPLE 7

[0052] In vitro Absorption Rates of Photocured Films

[0053] Thin films such as the one described in Example 6 made fromcoumarin ester endcapped polymers C, L, N, O, P, Q, and R, in Table 1were immersed in phosphate buffered saline pH 7.4 at 37° C. The filmswere removed and weighed once a week. The PBS buffer was also changedweekly. The absorption profiles of these films is plotted in FIG. 2. Itis clearly evident from this graph that the absorption of thesepolymeric networks can be controlled by their overall chemicalcomposition. As expected, the material containing some poly(ethyleneglycol) degraded most rapidly.

EXAMPLE 8

[0054] Microparticle Formation

[0055] Coumarin endcapped, liquid copolymer L of Table 1 was dissolvedin a mixture of dioxane and water and poured into a beaker containingliquid paraffin containing 0.2% sorbitan trioleate and a magneticstirring bar. The mixture was stirred at 200 rpm's and irradiated withultraviolet light for thirty minutes at an intensity of 10.8 mW/cm². Themicroparticles were isolated by filtration and washed thoroughly withn-hexane. The microspheres contained about 5% water.

[0056] The same experiment was repeated using coumarin endcapped, liquidcopolymer R of Table 1. In this case, the resulting microsherescontained about 10% water which is expected based on the increasedhydrophilicity of this material due to the incorporation ofpoly(ethylene glycol) in the network.

EXAMPLE 9

[0057] Surface Modification

[0058] On a primed cover glass, a thin layer of coumarin ester endcappedliquid absorbable polymer L from Table 1 was applied. The primer was athin layer of poly[2-(7-coumaryloxy)ethyl methacrylate-co-dimethylacrylamide] that was subsequently irradiated to form a highlycrosslinked, coumarinated surface. A computer controlled ultraviolet penlight (Hg—Xe lamp/light width=1.0 mm) moving at 10 microns per secondirradiated the substrate in the shape of a square. After ten cycles, theuncured liquid polymer was dissolved away using dichloromethane, and thesubstrate dried. As shown in FIG. 3, upon inspection using scanningelectron microscopy, a square shape was observed on the surface; itsline width was about 0.9 mm and its height above the substrate's surfacewas approximately 400 microns. This experiment demonstrates the use ofthe coumarin ester endcapped, liquid absorbable polymers as surfacecoatings, either as a uniform coating or one with specific topologyincorporated on the surface. In the field of implantable medicaldevices, there are advantages to presenting the right surface topologyto the surrounding tissue to reduce inflammation and to encouragecellular attachment to the device; this cellular attachment isespecially important when the device is a tissue engineering scaffold.In addition, it has been shown that these same coumarin ester endcappedmaterials can be used as a resin in a stereolithography apparatus.

We claim:
 1. A fluid prepolymer comprising a polymer prepared from atleast one lactone monomer selected from the group consisting ofε-caprolactone, trimethylene carbonate, glycolide, L-lactide, D-lactide,DL-lactide, p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one,1,4-dioxepan-2-one and 1,5-dioxepan-2-one, said prepolymer being aliquid at 65° C. or at a lower temperature and comprising coumarin esterendgroups, wherein the inherent viscosity of the polymer is betweenabout 0.05 dL/g and about 0.8 dL/g as determined in a 0.1 g/dL solutionof hexafluoroisoproanol at 25° C.
 2. The fluid prepolymer of claim 1wherein the polymer is liquid at 25° C.
 3. The fluid prepolymer of claim1 wherein the polymer is selected from the group consisting of poly[ε-caprolactone-co-trimethylene carbonate],poly[ε-caprolactone-co-glycolide], poly[ε-caprolactone-co-L-lactide],poly[ε-caprolactone-co-DL-lactide], poly[5-caprolactone-co-D-lactide],poly[ε-caprolactone-co-p-dioxanone],poly[[ε-caprolactone-co-5,5-dimethyl-1,3-dioxan-2-one],poly[ε-caprolactone-co-1,4-dioxepan-2-one],poly[ε-caprolactone-co-1,5-dioxepan-2-one], poly(trimethylenecarbonate), poly(ε-caprolactone), poly[trimethylenecarbonate-co-p-dioxanone], and poly[trimethylenecarbonate-co-5,5-dimethyl-1,3-dioxan-2-one].
 4. The fluid prepolymer ofclaim 1 wherein the polymer is branched.
 5. The fluid prepolymer ofclaim 4 wherein the polymer is synthesized using an initiator selectedfrom the group consisting of trimethylolpropane, pentaerythritol, linearpoly(ethylene glycol)s, branched poly(ethylene glycol)s, oligomericpoly(2-hydroxyethyl methacrylate) and its copolymers with other vinylmonomers, poly(vinyl alcohol) and poly(vinyl acetate-co-vinyl alcohol).6. The fluid prepolymer of claim 1 wherein said fluid prepolymer hasbeen irradiated with ultraviolet light, thereby forming a polymericnetwork.
 7. The fluid prepolymer of claim 1 wherein droplets of saidfluid prepolymer have been irradiated with ultraviolet light, therebyforming microparticles.
 8. The fluid prepolymer of claim 1 furthercomprising at least one bioactive compound in a therapeuticallyeffective amount.
 9. The fluid prepolymer of claim 8 wherein the polymeris liquid at 25° C.
 10. The fluid prepolymer of claim 8 wherein thepolymer is selected from the group consisting ofpoly[ε-caprolactone-co-trimethylene carbonate],poly[ε-caprolactone-co-glycolide], poly[ε-caprolactone-co-L-lactide],poly [ε-caprolactone-co-DL-lactide], poly[ε-caprolactone-co-D-lactide],poly[ε-caprolactone-co-p-dioxanone],poly[[ε-caprolactone-co-5,5-dimethyl-1,3-dioxan-2-one],poly[ε-caprolactone-co-1,4-dioxepan-2-one],poly[ε-caprolactone-co-1,5-dioxepan-2-one], poly(trimethylenecarbonate), poly (ε-caprolactone), poly[trimethylenecarbonate-co-p-dioxanone], and poly[trimethylenecarbonate-co-5,5-dimethyl-1,3-dioxan-2-one].
 11. The fluid prepolymer ofclaim 8 wherein the polymer is branched.
 12. The fluid prepolymer ofclaim 11 wherein the polymer is synthesized using an initiator selectedfrom the group consisting of trimethylolpropane, pentaerythritol, linearpoly(ethylene glycol)s, branched poly(ethylene glycol)s, oligomericpoly(2-hydroxyethyl methacrylate) and its copolymers with other vinylmonomers, poly(vinyl alcohol) and poly(vinyl acetate-co-vinyl alcohol).13. The fluid prepolymer of claim 8 wherein said fluid prepolymer isirradiated with ultraviolet light, thereby forming a polymeric network.14. The fluid prepolymer of claim 8 wherein droplets of said fluidprepolymer are irradiated with ultraviolet light, thereby formingmicroparticles.
 15. The fluid prepolymer of claim 1 further comprisingat least one inorganic compound.
 16. The fluid prepolymer of claim 15wherein the polymer is liquid at 25° C.
 17. The fluid prepolymer ofclaim 15 wherein the polymer is selected from the group consisting ofpoly[ε-caprolactone-co-trimethylene carbonate],poly[ε-caprolactone-co-glycolide], poly[ε-caprolactone-co-L-lactide],poly[ε-caprolactone-co-DL-lactide], poly[ε-caprolactone-co-D-lactide],poly[ε-caprolactone-co-p-dioxanone],poly[[ε-caprolactone-co-5,5-dimethyl-1,3-dioxan-2-one],poly[ε-caprolactone-co-1,4-dioxepan-2-one],poly[ε-caprolactone-co-1,5-dioxepan-2-one], poly(trimethylenecarbonate), poly(ε-caprolactone), poly[trimethylenecarbonate-co-p-dioxanone], and poly(trimethylenecarbonate-co-5,5-dimethyl-1,3-dioxan-2-one].
 18. The fluid prepolymer ofclaim 15 wherein the polymer is branched.
 19. The fluid prepolymer ofclaim 18 wherein the polymer is synthesized using an initiator selectedfrom the group consisting of trimethylolpropane, pentaerythritol, linearpoly(ethylene glycol)s, branched poly(ethylene glycol)s, oligomericpoly(2-hydroxyethyl methacrylate) and its copolymers with other vinylmonomers, poly(vinyl alcohol) and poly(vinyl acetate-co-vinyl alcohol).20. The fluid prepolymer of claim 15 wherein said fluid prepolymer isirradiated with ultraviolet light, thereby forming a polymeric network.21. The fluid prepolymer of claim 15 wherein droplets of said fluidprepolymer are irradiated with ultraviolet light, thereby formingmicroparticles.
 22. The fluid prepolymer of claim 15 wherein theinorganic filler is selected from the group consisting ofalpha-tricalcium phosphate, beta-tricalcium phosphate, calciumcarbonate, barium carbonate, calcium sulfate, barium sulfate andhydroxyapatite.
 23. The fluid prepolymer of claim 22 wherein theinorganic filler is a polymorph of calcium phosphate.
 24. The fluidprepolymer of claim 22 wherein the inorganic filler is hydroxyapatite.25. The fluid prepolymer of claim 15 further comprising a bioactivecompound in a therapeutically effective amount.
 26. The fluid prepolymerof claim 25 wherein the bioactive compound is a growth factor.
 27. Amethod of modifying a surface of a substrate, comprising: forming a filmof a fluid prepolymer of claim 1 on a surface of a substrate; andirradiating said film with ultraviolet light to form a crosslinkedcoating.
 28. The method of claim 27 wherein a template is used to directthe ultraviolet light only to designated areas on the surface of saidsubstrate, thereby creating specific surface architecture.
 29. Themethod of claim 27 wherein the method is carried out sequentially,thereby producing distinct layers on the surface of the substrate. 30.The method of claim 27 wherein a mixture of fluid prepolymers of claim 1are used.
 31. The method of claim 27 wherein the substrate is selectedfrom the group consisting of a medical device, a tissue engineeringscaffold, and a drug delivery system.
 32. The method of claim 30 whereinthe device is selected from the group consisting of plates, screws,pins, rods, nails, rivets, clips, suture anchors, staples, stents andcatheters.
 33. The method of claim 27 wherein said fluid prepolymerfurther comprises at least one bioactive compound in a therapeuticallyeffective amount.
 34. The method of claim 32 wherein a template is usedto direct the ultraviolet light only to designated areas on the surfaceof the substrate, thereby creating specific surface architecture. 35.The method of claim 33 wherein a mixture of fluid prepolymers of claim 1are used.
 36. The method of claim 33 wherein the method is carried outsequentially, thereby producing distinct layers on the surface of thesubstrate.
 37. The method of claim 27 wherein the substrate is selectedfrom the group consisting of a medical device, a tissue engineeringscaffold, and a drug delivery system.
 38. The method of claim 37 whereinthe substrate is selected from the group consisting of plates, screws,pins, rods, nails, rivets, clips, suture anchors, staples, stents andcatheters.
 39. A method of forming medical implants, comprising:irradiating the fluid prepolymer of claim 1 in vivo.
 40. The method ofclaim 39 wherein the implant is selected from the group consisting of anadhesion prevention barrier, a tissue bulking agent, a defect filler, asurgical sealant and a surgical pledget.
 41. The method of claim 39wherein said fluid prepolymer further comprises at least one bioactivecompound in a therapeutically effective amount.
 42. The method of claim41 wherein the implant is selected from the group consisting of anadhesion prevention barrier, a tissue bulking agent, a defect filler, asurgical sealant and a surgical pledget.
 43. A method of repairing bonydefects, comprising: filling empty spaces within a bone with the fluidprepolymer of claim 15 during an operation; and then irradiating saidfluid prepolymer in vivo, thereby forming a polymeric network in vivo.44. The method of claim 43 wherein bone fragments are incorporated intothe fluid prepolymer prior to filling said empty spaces.
 45. A method ofmanufacturing medical devices using the fluid prepolymer of claim 1 in astereolithography apparatus.